This proposal is designed to provide the principal investigator with the knowledge and experience necessary for his development as an independent clinical researcher in the fields of nephrolithiasis and bone and calcium metabolism. The research plan in this application proposes to explore the metabolic consequences of the popular low-carbohydrate high-protein (LCHP) diet that is widely used for weight reduction. The diet imposes a limitation on carbohydrate intake, which leads to an obligatory increase in protein consumption. Excessive intake of dietary proteins has long been known to significantly raise the urinary excretion of calcium, increasing the risk for kidney stone formation and possibly causing bone loss. The objectives of the research plan are to shed light on the mechanism(s) underlying the increased calcium excretion associated with the LCHP diet. We hypothesize that LCHP diets induce hypercalciuria by acid load, high urinary prostaglandin E2 (PGE2), or both. The first specific aim tests the hypothesis that the observed hypercalciuria is caused by an acid load conferred by the diet. We will explore the ability of potassium citrate, an alkali potassium salt, to either partially or completely reverse the hypercalciuria induced by the LCHP diet by neutralizing the conferred acid load. The second specific aim will test the hypothesis that the hypercalciuria occurs through a mechanism that increases the urinary excretion of prostaglandin E2 (PGE2). We will test the ability of indomethacin to reverse the hypercalciuria induced by the LCHP diet, by altering PGE2 production. A better understanding of the mechanism(s) of dietary protein-induced hypercalciuria will be valuable in exploring the safety and the potential deleterious effects of the popular LCHP diet on the skeleton and the kidney. In addition to the research plan, the applicant proposes to further his research career by collaborating with basic researchers working on the same area in animals, attending didactic courses in clinical research conduct, and learning the techniques of bone biopsy evaluation.